This invention relates to the purification of tertiary formamides such as dimethylformamide that are contaminated with tertiary acetamides such as dimethylacetamide. The invention further relates to improved methods of chlorinating sucrose-6-acylates, which are useful intermediates in the production of sucralose.
Sucralose (4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), a high-intensity sweetener made from sucrose, can be used in many food and beverage applications.

A number of different synthesis routes for the preparation of sucralose have been developed in which the reactive hydroxyl in the 6 position is first blocked with an acyl group to form a sucrose-6-acylate. The acyl group can be any acyl group that serves to protect the 6-hydroxy group during chlorination. It is preferably an aliphatic or carbocyclic aromatic acyl group, more preferably a benzoyl or acetyl group, and most preferably an acetyl group. The sucrose-6-acylate is chlorinated to replace the hydroxyl groups at the 4,1′ and 6′ positions with chlorine atoms to produce 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose 6-acylate (referred to herein as sucralose-6-acylate), followed by hydrolysis to remove the acyl substituent and thereby produce sucralose. Several synthesis routes for formation of the sucrose-6-acylates involve tin-mediated acylation reactions, with illustrative examples being disclosed in U.S. Pat. Nos. 4,950,746; 5,023,329; 5,089,608; 5,034,551; and 5,470,969, all of which are incorporated herein by reference in their entirety for all purposes.
Various chlorinating agents may be used to chlorinate the sucrose-6-acylate, and most commonly a Vilsmeier-type salt such as Arnold's Reagent (N,N-dimethylchloroformiminium chloride) will be used. One suitable chlorination process is disclosed by Walkup et al. (U.S. Pat. No. 4,980,463), incorporated herein by reference in its entirety for all purposes. This process uses a tertiary formamide, typically N,N-dimethyl formamide (“DMF”), as the chlorination reaction solvent. After the chlorination is complete, adducts of Arnold's Reagent on the base sucrose moiety and excess chlorinating reagent are neutralized (“quenched”) with aqueous base to provide the sucralose-6-acylate in an aqueous solution, accompanied by the tertiary amide solvent and salts resulting from reactions of the chlorination reagent. The sucralose-6-acylate is then deacylated to produce sucralose. One suitable deacylation process is taught by Navia et al., U.S. Pat. No. 5,498,709, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes.
In commercial processes, it will be economically desirable to recover the tertiary formamide solvent from sucrose-6-acylate reaction product mixtures (either directly after chlorination or after one or more subsequent processing/reaction steps) and then recycle such recovered tertiary formamide for use as a reaction vehicle (e.g., as a reaction vehicle for the sucrose-6-acylate chlorination and/or the esterification of sucrose to obtain the sucrose-6-acylate). As used herein, the term “reaction vehicle” means a diluent or solvent in which a reaction is carried out; the diluent or solvent does not necessarily fully dissolve all the components being reacted or all the products produced in the reaction. However, depending upon the particular reagents and processing conditions selected, the recovered tertiary formamide is typically contaminated with varying amounts of tertiary acetamides such as dimethylacetamide (“DMAc”), which can be formed as a process by-product. The level of DMAc tends to build up over time as the tertiary formamide is recycled and reused.
We have now discovered that the presence of DMAc as a contaminant in the DMF used as a reaction vehicle when chlorinating a sucrose-6-acylate has a significant, adverse effect on the yield of the desired chlorination product. For every 1 weight % of DMAc present in the DMF, a product yield loss of approximately 8 to 10% is observed (i.e., the yield decreases from ca. 60% to ca. 50-52%) when carrying out a chlorination process in accordance with the process described in the aforementioned Walkup et al. patent. This suggests that DMAc actively participates in some way during such chlorination so as to interfere with the desired conversion of hydroxyl groups in the sucrose-6-acylate to chloride groups. The adverse effect of DMAc on the product yield obtained when chlorinating a sucrose-6-acylate using DMF as a reaction vehicle was surprising, in view of the fact that tertiary amides in general have previously been proposed as suitable solvents for use in such a chlorination process.
We have now found that reducing the level of DMAc in a DMF-containing stream recovered from a sucrose-6-acylate chlorination process prior to reusing that stream as a reaction vehicle provides enhancements in the yield of the desired sucralose-6-acylate. That is, managing the DMAc content in such a recycle stream helps to ensure that the sucralose-6-acylate yield remains about the same as it would be using pure DMF as a reaction vehicle. Unfortunately, because DMF and DMAc have similar properties and close boiling points (153° C. and 166° C. respectively, at atmospheric pressure), purifying the recovered DMF stream by fractional distillation is difficult, energy intensive, and requires expensive distillation equipment, thereby increasing the cost of manufacturing sucralose.
Accordingly, it would therefore be quite desirable to develop alternative, less expensive methods of purifying DMF to remove DMAc or to develop ways of using DMAc-contaminated DMF in a sucrose-6-acylate chlorination process while preserving the yields that are possible when pure DMF is used as solvent.